Enantiomers of 6-[(4-chloro-phenyl)- hydroxy-(3-methyl-3h-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1- methyl-1h-quinolin-2-one and salts thereof, useful in the treatment of cancer

ABSTRACT

This invention relates to the enantiomers of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-y)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl) -phenyl]-1-methyl-1H-quinolin-2-one, prodrugs thereof, and pharmaceutically acceptable salts and solvates of said compounds and said prodrugs, that are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. The invention also relates to processes for the production of enantiomerically pure or optically enriched (+)- or (−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl )-phenyl]-1 -methyl-1H-quinol in-2-one enantiomers from a mixture containing two enantiomers using continuous chromatography. The invention further relates to the L-(+)-tartaric acid or (S)-(−)-1 1&#39;-binapthyl-2,2&#39;-diyl hydrogenphosphate salts of (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional PatentApplication No. 60/315,740, filed Aug. 29, 2001, the contents of whichare hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] This invention relates to the enantiomers of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one, prodrugs thereof andpharmaceutically acceptable salts and solvates of said enantiomers andprodrugs. The compounds of the present invention are useful in thetreatment of hyperproliferative diseases, such as cancers, in mammals.The compounds are also useful as inhibitors of the enzyme farnesylprotein transferase, which is involved in cancerous tumor growth.

[0003] In describing an optically active compound, the prefixes D and Lor R and S are used to denote the absolute configuration of the moleculeabout its chiral center(s). The prefixes (+) and (−) or d or I areemployed to designate the sign of rotation of plane-polarized light bythe compound, with (−) or I meaning that the compound is levorotatoryand with (+) or d meaning that the compound is dextrotatory. For a givenchemical structure the optically active isomers having opposite sign ofoptical rotation are called enantiomers. Said enantiomers are identicalexcept that they are mirror images of each other. A 1:1 mixture of suchenantiomer is called a racemic mixture.

[0004] It should be noted that optical rotation of chemical substancesis dependent upon experimental parameters. The values shown hereinunderare specific rotations and the experimental conditions such astemperature, the wavelength of the plane polarized light used, thesolvent as well as the concentration of the sample are indicated in theconventional way. The optical rotation may vary when for instance anacid addition salt is formed.

[0005] Stereochemical purity is of importance for biologically activesubstances that are used in pharmaceutical compositions for humanapplication since the respective enantiomers may have a differentpotency or may have a different activity. Often, one of the enantiomerspresents the desired optimum biological activity. Additionally, thepresence of the other enantiomer in a composition or agent may cause orinvigorate certain side effects. It is generally desirable to administerthe biologically active substance in the form of a substantially pureenantiomer, which specifically exhibits the desired biological activity.Therefore, the resolution of a racemate into its enantiomers is often animportant step in the preparation process of pharmacologically activesubstances.

[0006] The present invention provides for the enantiomers (−)- and(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but--1-ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one, and derivatives thereof. Theinvention further provides a number of processes to isolate theenantiomers (-)- and (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl )-methyl]-4-[3-(3-hydroxy-3-methyl-but- 1-ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one, and the derivatives thereof,in high yields and in a high enantiomeric excess (e.e.). Moreparticularly, the invention relates to the process for production ofenantiomerically pure and/or optically enriched (−)- and(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yI)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one from a racemate mixtureusing continuous chromatography or chiral salt precipitation methods.

SUMMARY OF THE INVENTION

[0007] The invention relates to(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinol in-2-one and(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one, prodrugs thereof andpharmaceutically acceptable salts and solvates of said compounds andprodrugs.

[0008] The present invention further relates to(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1 -ynyl)-phenyl]-1-methyl-1 H-quinol in- 2-one, L-(+)-tartaric acid and(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1 -ynyl)-phenyl]-1-methyl-1H-quinol in-2-one, (S)-(−)- 1 ,1'-binapthyl-2,2'-diyl hydrogenphosphate.

[0009] This invention also relates to a method for the treatment ofabnormal cell growth in a mammal, including a human, comprisingadministering to said mammal an amount of one of the compounds describedherein, prodrugs thereof, and pharmaceutically acceptable salts andsolvates of said compounds and prodrugs, that is effective in treatingabnormal cell growth or inhibiting farnesyl protein transferase.

[0010] In one embodiment of this method, the abnormal cell growth iscancer, including, but not limited to, lung cancer, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, uterine cancer, ovarian cancer, rectal cancer,cancer of the anal region, stomach cancer, colon cancer, breast cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, carcinoma of the cervix, carcinoma of the vagina, carcinomaof the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of thesmall intestine, cancer of the endocrine system, cancer of the thyroidgland, cancer of the parathyroid gland, cancer of the adrenal gland,sarcoma of soft tissue, cancer of the urethra, cancer of the penis,prostate cancer, chronic or acute leukemia, lymphocytic lymphomas,cancer of the bladder, cancer of the kidney or ureter, renal cellcarcinoma, carcinoma of the renal pelvis, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, spinal axis tumors, brainstem glioma, pituitary adenoma, or a combination of one or more of theforegoing cancers. In another embodiment of said method, said abnormalcell growth is a benign proliferative disease, including, but notlimited to, psoriasis, benign prostatic hypertrophy or restinosis.

[0011] This invention also relates to a method for the treatment ofabnormal cell growth in a mammal which comprises administering to saidmammal a therapeutically effective amount of one of the compoundsdescribed herein, prodrugs thereof, and pharmaceutically acceptablesalts and solvates of said compounds and prodrugs in combination with ananti-tumor agent selected from the group consisting of mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, anti-hormones,and anti-androgens.

[0012] The present invention also relates to a method for the treatmentof an infection in a mammal, including a human, that is facilitated byfarnesyl protein transferase, such as hepatitis delta virus or malaria,which comprises administering to said mammal a therapeutically effectiveamount of one of the compounds described herein, prodrugs thereof, andpharmaceutically acceptable salts and solvates of said compounds andprodrugs.

[0013] This invention also relates to a pharmaceutical composition forthe treatment of abnormal cell growth in a mammal, including a human,comprising an amount of one of the compounds described herein, prodrugsthereof, and pharmaceutically acceptable salts and solvates of saidcompounds and prodrugs, that is effective in inhibiting farnesyl proteintransferase, and a pharmaceutically acceptable carrier.

[0014] This invention also relates to a pharmaceutical composition forthe treatment of abnormal cell growth in a mammal, including a human,comprising an amount of one of the compounds described herein, prodrugsthereof, and pharmaceutically acceptable salts and solvates of saidcompounds and prodrugs, that is effective in treating abnormal cellgrowth, and a pharmaceutically acceptable carrier.

[0015] The invention also relates to a pharmaceutical composition forthe treatment of abnormal cell growth in a mammal, including a human,which comprises a therapeutically effective amount of one of thecompounds described herein, prodrugs thereof, and pharmaceuticallyacceptable salts and solvates of said compounds and prodrugs, incombination with a pharmaceutically acceptable carrier and an anti-tumoragent selected from the group consisting of mitotic inhibitors,alkylating agents, anti-metabolites, intercalating antibiotics, growthfactor inhibitors, cell cycle inhibitors, enzymes, topoisomeraseinhibitors, biological response modifiers, anti-hormones, andanti-androgens.

[0016] This invention also relates to a pharmaceutical composition forthe treatment of an infection in a mammal, including a human, that isfacilitated by farnesyl protein transferase, such as malaria orhepatitis delta virus, comprising an amount of effective amount of oneof the compounds described herein, prodrugs thereof, andpharmaceutically acceptable salts and solvates of said compounds andprodrugs, that is effective in treating abnormal cell growth, and apharmaceutically acceptable carrier.

[0017] This invention also relates to processes for resolving theracemate6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one into its two enantiomers,(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1 -ynyl)-phenyl]-1 -methyl-1H-quinolin-2-one and(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one,using either batch or continuous chromatography or salt crystallization.

[0018] The present invention also relates to a process forchromatographically resolving an enantiomerically pure or opticallyenriched(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2- one or(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-onefrom a racemic mixture using continuous chromatography or single columnhigh performance chromatography.

[0019] Some examples of continuous chromatography are liquidchromatography technologies known by the names cyclojet, and simulatedmoving bed chromatography (SMB). The concept of SMB was described in thelate 1950's (U.S. Pat. No. 2,957,927 and 2,985,589) and has long beenused in the petrochemical and sugar industries, Nicoud, R. M., LC-GCIntl, 5 (5), 43 (1992). Further reference can be made to U.S. Pat. Nos.3,205,166; 3,291,726; and 3,310,486. A high efficiency continuousseparation process using SMB is disclosed in U.S. Patents 4,402,832;5,518,625; 5,434,298; 5,434,299; 5,498,752; and Re 35,919, which are allincorporated by reference. In addition, “Chiral Discrimination onPolysaccharide Derivatives”, Yashima and Okamoto, Bull. Chem. Soc. Jpn.,68, 3289- 3307(1995) discusses separation characteristics useful inchiral chromatography phases. Further discussion by Okamoto et. al. areincluded in The Journal of Chromatography, Part A, Volume 694, pp 101-109 (1995).

[0020] SMB combines the high-resolution power of high performance liquidchromatography (HPLC) with the lower costs of classical separationprocesses such as crystallization. The costs of the SMB process can bereduced even further, if it is combined with a racemization stepconverting the undesired enantiomer into the racemic form, which couldthen be recycled back into the process to isolate more of the desiredenantiomer. This results in a very efficient and productive method toisolate a desired enantiomer from a racemic mixture.

[0021] Other methods may also be employed to separate enantiomers suchas the classic technique of chiral acid precipitation, which isdescribed in applications EP 828,702 and WO 00/32554 and U.S. Pat. No.4,571,424. The aforementioned applications and U.S. patent are herebyincorporated in their entirety by reference. Separation of enantiomersusing chiral acids has been found by those of ordinary skill in the artto be a matter of trial and error. It is common even for experiencedinvestigators to find that despite using a multitude of combinations ofresolving agents and reaction conditions that chiral acid preparation isunsuccessful. The present invention provides a chiral acid precipitationof the enantiomers of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-onein high enantiomeric excess and high optical purity.

[0022] The methods of the present invention are a substantialimprovement over the method described in the '377 patent for preparingoptically enriched6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1 H-quinolin-2-one. The method described in Example 2 of the'377 patent employed high-performance liquid chromatography overCHIRALPAK® AD. Both enantiomers were obtained with greater than 97%optical purity. The methods of the present invention involve ansignificant improvement of the method described in the '377 patent byproviding stereoselective preparations which provide the desiredenantiomers at very high purity levels in a cost effective manner. Themethods of the present invention are particularly attractive for use inthe commercial production of enantiomers of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one and the conversion of saidenantiomers to either (-)- or(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1 -methyl-1H-quinolin-2-one. Conversion of the isolated enantiomer to a desiredsalt form can be readily achieved.

[0023] The continuous chromatography comprises a liquid mobile phasecomprising at least one polar solvent and a solid chiral stationaryphase comprising a derivatized polysaccharide that is selected from theamylosic or cellulosic class of polysaccharides.

[0024] Some examples of the continuous chromatography methods aresimulated moving bed chromatography process or the cyclojet process. Thesimulated moving bed chromatography process is preferred. The processuses a chiral stationary phase which is a member of the amylosic orcellulosic class of polysaccharides selected from amylose 3,4-substituted phenyl carbamate, cellulose 3, 5-disubstituted phenylcarbamate or cellulose 4-substituted benzoate. Preferably the chiralstationary phase is an analog of amylose tris (3,5-substituted phenylcarbamate) wherein the substituent is 3, 5-dimethyl. The chiralstationary phase can also preferably be a cellulose 3, 5-disubstitutedphenyl carbamate or cellulose 4- substituted benzoate polysaccharideanalog. Preferably the chiral stationary phase is cellulose tris(3,5-dimethylphenyl) carbamate or cellulose tris (4-methylbenzoate).

[0025] The mobile phase comprises a solvent that is selected fromheptane, hexane, isopropyl, ethanol, methanol, methyl acetate,acetonitrile, methylene chloride, ethyl acetate and/or mixtures thereof.Preferably the mobile phase is selected from mixture of heptane andethanol or isopropanol and/or a mixture of methanol and ethanol with orwithout heptane. In one embodiment the chiral stationary phase isamylose tris(3,5-dimethylphenylcarbamate) with a mobile phase 50:50 ofheptane and ethanol. In one preferred embodiment the chiral stationaryphase is amylose tris(3,5-dimethylphenylcarbamate) and the mobile phaseis 50:50 mixture of methanol and ethanol. The chromatographic retentiontimes are increased or decreased by varying the mobile phase components.The separation affords at least one of the enantiomers recovered isgreater than or equal to 90 percent. The temperature range is about 5 to45° C., preferably 20 to 40° C., more preferably 25° C. The separationfactor alpha “α” is about 1.1 to 4.0. Using a temperature of about 25°C. takes advantage of an increased solubility of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-onein the mobile phase. The chiral stationary phase polysaccharidederivative can also be immobilized on silica gel, zirconium, alumina,ceramics and other silicas.

[0026] The invention also relates to the salt separation of theenantiomers6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one using L-(+)-tartaric acid or(S)-(−)-1,1'-binapthyl-2,2'-diyl hydrogenphosphate salts.

[0027] “Abnormal cell growth”, as used herein, unless otherwiseindicated, refers to cell growth that is independent of normalregulatory mechanisms (e.g., loss of contact inhibition). This includesthe abnormal growth of: (1) tumor cells (tumors) expressing an activatedRas oncogene; (2) tumor cells in which the Ras protein is activated as aresult of oncogenic mutation in another gene; (3) benign and malignantcells of other proliferative diseases in which aberrant Ras activationoccurs; and (4) any tumors that proliferate by virtue of farnesylprotein transferase.

[0028] The term “treating”, as used herein, unless otherwise indicated,means reversing, alleviating, inhibiting the progress of, or preventingthe disorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above.

[0029] The term “pharmaceutically acceptable salt(s)”, as used herein,unless otherwise indicated, includes salts of acidic or basic groupsthat may be present in the compounds of present invention. For example,pharmaceutically acceptable salts include sodium, calcium and potassiumsalts of carboxylic acid groups and hydrochloride salts of amino groups.Other pharmaceutically acceptable salts of amino groups arehydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate,dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate,mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate)salts. The preparation of such salts is described below.

[0030] The term “prodrug”, as used herein, unless otherwise indicated,means compounds that are drug precursors, which followingadministration, release the drug in vivo via some chemical orphysiological process (e.g., a prodrug on being brought to thephysiological pH is converted to the desired drug form).

[0031] The free hydroxy group of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one or(-)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-onecan be converted into a prodrug. Prodrugs include compounds wherein anamino acid residue, or a polypeptide chain of two or more (e.g., two,three or four) amino acid residues is covalently joined through thehydroxy group of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl )-phenyl]-1 -methyl-1H-quinolin-2-one or (−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one. The amino acid residuesinclude but are not limited to the 20 naturally occurring amino acidscommonly designated by three letter symbols and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta- alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

[0032] Additional types of prodrugs are also encompassed. For instance,the free hydroxy group may be derivatized using groups including but notlimited to hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in D. Fleisher, R. Bong,B.H. Stewart, Advanced Drug Delivery Reviews (1996) 19, 115. Carbamateprodrugs of hydroxy are also included, as are carbonate prodrugs andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or where heacyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in R.P. Robinson etal., J. Medicinal Chemistry (1996) 39, 10.

[0033] The subject invention also includes isotopically-labelledcompounds, and the pharmaceutically acceptable salts thereof, which areidentical to(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-methyl-1H-quinolin-2-one or(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one,but for the fact that one or more atoms are replaced by an atom havingan atomic mass or mass number different from the atomic mass or massnumber usually found in nature. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, and ³⁶Cl,respectively. Compounds of the present invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ³H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1 -ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one or(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one,and prodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the Schemes and/or in the Examples andPreparations of the '377 patent by substituting a readily availableisotopically labelled reagent for a non-isotopically labelled reagent.

[0034] It will be appreciated that any solvate (e.g. hydrate) form of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one or(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one and prodrugs thereof can beused for the purpose of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0035] The present invention provides for the enantiomers(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl )-phenyl]-1-methyl -1 H-quinolin-2-one and(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1H-quinolin-2-one, prodrugs thereof andpharmaceutically acceptable salts and solvates of said enantiomers andprodrugs that are useful in the treatment of hyperproliferativediseases, such as cancers, in mammals.

[0036] The invention also relates to the L-(+)-tartaric acid or(S)-(−)-1,1′-binapthyl-2,2′-diyl hydrogenphosphate salts of the(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]- 1-methyl-1 H-quinolin-2-one.

[0037] The preparation of the racemate6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1 -ynyl)-phenyl]- 1-methyl-1H-quinolin-2-one may be prepared in themanner described in Example 4 of United States Patent No. 6,150,377(“the '377 patent”) by replacing 3-methyl-1-butyne with3-hydroxy-3-methyl-1-butyne. The '388 patent is hereby incorporated byreference in its entirety. The racemate6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-methyl-1H-quinolin-2-oneis useful in the preparation of the cancer treating compound6-[(4-chloro-phenyl)-hydroxy-(3-methyl]-1 H-quinolin-2-one which is alsodescribed in U.S. Pat. No. 6,150,377 (“the '377 patent”), which ishereby incorporated by reference in its entirety. The racemate,6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,its enantiomers and pharmaceutically acceptable salts are also useful asinhibitors of the enzyme farnesyl protein transferase.

[0038] The '377 patent also describes the separation of the enantiomersof the racemate 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1 H-quinolin-2-one using high performance liquidchromatography (HPLC). However, the '377 patent does not specificallydescribe the separation of the enantiomers of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one.6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one has one chiral center and thus exists in twoenantiomeric forms, i.e., (+) or (−).

[0039] The racemate,6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one,may be separated into its two enantiomers using chromatographytechniques, such as high performance liquid chromatography (HPLC) orsimulated moving bed chromatography (SMB). The separated enantiomers of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one may be converted if desiredinto the corresponding enantiomers of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one.Salt forms of the free bases6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-oneand6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-oneare readily prepared and are useful in the treatment ofhyperproliferative diseases, such as cancers, in mammals, especiallyhumans.

[0040] If the preparation of an optically enriched enantiomer of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1 H-quinolin-2-one is desiredthe methods of the present invention offer significant advantages overthe method disclosed in the '377 patent. Once the desired enantiomer hasbeen isolated it can be readily converted into a desired salt. It isadvantageous to resolve a racemcate into its enantiomers at the earlieststage of the synthesis in order to minimize the amount of superfluousballast carried through the reaction sequence. The '377 patent describesthe separation of the enantiomers of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)methyl]-4-(3-ethynyl-phenyl-1-methyl-1H-quinolin-2-onefollowed by conversion to the desired salt. The penultimate racemateformed in the synthesis of[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1 H-quinolin-2-one is6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one. No resolution of thepenultimate racemate or its derivatives thereof have been describedpreviously.

[0041] It has been found that racemate resolution of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl )-phenyl]-1-methyl-1 H-quinolin-2-one can be carried out by saltresolution and chromatographic methods. Each of the methods providesignificant advantages over the previously disclosed separation of theracemate6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-onein the '377 patent.

[0042] More particularly it has been found that using chromatographicmethods described below results in a surprising enhancement inproductivity thus providing more enantiomer per kg of chiral stationaryphase. This has significant economic benefits over the disclosedresolution of enantiomers in the '377 patent. This provides a commercialattractive method in which to prepare the enantiomers6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1 -ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one. The enantiomers of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one can be readily converted to the enantiomers of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one.Additionally, racemization of the undesired6-[4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one enantiomer is more facilethan that of corresponding undesired6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1 H-quinolin-2-one enantiomerdue to the protection of the alkynyl hydrogen.

[0043] Furthermore, single enantiomers are more soluble than theirracemic forms and thus downstream reactions can be more concentrated andhave higher volumetric productivity (further improved by the fact thatonly the desired isomer is being carried forward). This significantlyimproves the economics of the resolution.

[0044] Chromatography comprises a liquid mobile phase comprising atleast one polar solvent and a solid chiral stationary phase (CSP)comprising a derivatized polysaccharide that is selected from theamylosic or cellulosic class of polysaccharides. The amylosic orcellulosic class of polysaccharides are selected from cellulosetribenzoate, cellulose tricarbamate, and amylose tricarbamate.Preferably the chiral stationary phase is an analog of amylose (3, 5-substituent phenyl carbamate) wherein the substituent is 3-methyl,5-methyl.

[0045] The mobile phase comprises a solvent that is selected fromheptane, hexane, isopropanol, ethanol, methanol, methyl acetate,acetonitrile, methylene chloride, ethyl acetate and/or mixtures thereof.Preferably the mobile phase is selected from ethanol, isopropanol,methanol or heptane and/or binary or ternary mixtures of the solvents. Alist of acceptable combinations of mobile phases and solvents is givenin Table I below. In one embodiment the chiral stationary phase isamylose tris(3,5-dimethylphenyl carbamate) with a mobile phase ofethanol/methanol wherein the percentage of ethanol in the mobile phasemixture is greater than 30%. Preferably the chiral stationary phase isamylose tris (3,5-dimethylphenyl carbamate) and the mobile phase isethanol/heptane wherein the percentage of ethanol in the mobile phasemixture is greater than 30%. The chromatographic retention times areincreased or decreased by varying the mobile phase components. Theseparation affords recovery of greater than or equal to 90 percent of atleast one of the enantiomers. The temperature range is about 5 to 45°C., preferably about 20 to 40° C., and more preferably about 22 to 30°C. The separation factor a is about 1.2 to 5.0, preferably about 1.5 to4, and more preferably about 2 to 4.

[0046] Using a temperature of about 25° C. takes advantage of anincreased solubility of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-onein the mobile phase. The chiral stationary phase polysaccharidederivative can be immobilized on silica gel, zirconium, alumina,ceramics and other silicas.

[0047] Examples of suitable CSP and mobile phases for the6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one are shown in the Table 1below. TABLE 1 CHIRAL STATIONARY PHASE MOBILE PHASE TEMP UV SELECTORMIXTURE ° C. (nm) α Amylose tris (3,5- Heptane/ ethanol 25 230 1.1-4.0dimethylphenyl Methanol/ ethanol carbamate) Methanol/ ethanol/ heptaneHeptane and isopropanol Cellulose tris (3,5- Heptane/ ethanol 25 230˜1.3 dimethylphenyl Heptane/ carbamate) isopropanol Cellulose tris (4-Heptane/ ethanol 25 230 1.1 methylbenzoate)

[0048] The UV Wavelength represents the detector wavelength used tomonitor the elution of the two enantiomers. Alpha “α” represents theseparation factor for the enantiomers of 6-5[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one separation using a single column which is 4.6mm ID ×250 mm.

[0049] Batch chromatographic purification is achieved using a systemcomprising a high pressure positive displacement pumping system, asample injection mechanism (either injection loop or pump), a packedcolumn containing the CSP, a UV detector and a mechanism to collectfractions. The column is equilibrated in the desired mobile phase andthen the sample is injected onto the column. The column effluent is thenmonitored at a UV wavelength where the product absorbs. As the firstenantiomer (less retained enantiomer) elutes a fraction containingpredominately the first enantiomer is collected. As the UV absorbance ofthe first enantiomer peak decreases, the effluent is then switched to asecond collection vessel, The second collection vessel collects theportion of the enantiomers that elude at around the same point, whichoccurs if separation factor is close to 1. As the absorbance due to thesecond enantiomer (more retained enantiomer) elute, the effluent is thenswitched to a third vessel to collect pure second enantiomer. When theabsorbance of the second enantiomer decreases to a low level, thefraction collection is stopped. Multiple cycles of injection andcollection are repeated until the desired amount of enantiomers iscollected.

[0050] Continuous chromatography can be utilized in the presentinvention to separate the enantiomers of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one. One example of continuous chromatography isthe cycloject method, which is described in U.S. Pat. No. 5,630,943,incorporated herein by reference. Another continuous chromatographicmethod that may be employed to separate the enantiomers of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-oneis Simulated Moving Bed Chromatography (SMB) as described in U.S. Pat.Nos. 5,470,464; 5,705,061; 5,422,077; 5,456,825 and EPO 586,385, each ofthe aforementioned U.S. patents and European application is incorporatedherein by reference.

[0051] SMB chromatography for the production of enantiomerically pureand/or optically enriched6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-onefrom a mixture containing two enantiomers is described below. Thepurification is achieved using SMB comprising a set of columns packedwith a chromatographic CSP capable of chiral recognition; ports for thecontinuous introduction of solvent desorbent (mobile phase) and feed;ports for the continuous removal of raffinate (solution containing theless strongly retained enantiomer) and extract (solution containing themore strongly retained enantiomer); and a means of recycling fluidthrough the system, if necessary. The columns are connected such thatthe outlet of each column is connected to the inlet of the next columnalso with the outlet of the last column being connected to the inlet ofthe first column.

[0052] The following general procedures for continuous chromatography inExamples of the present invention were followed. Using the experimentalconditions described herein it was found that the(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one enantiomer was more retainedand was recovered in the extract stream.

[0053] The optimization of the operating conditions of a SMB ispreferably done using a simulation tool, a methodology based on themodeling/simulation of non-linear chromatography as described in ChartonF., and Nicoud, R. M., J. Chrom., 702, 97-112 (1995).

[0054] In order to enhance productivity and yield of the enantiomerseparated using SMB racemization may be employed. Under the SMBconditions employed for the separation of the enantiomers of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one the (−) enantiomer was less retained. If the desiredenantiomer is the (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1 -ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one then the less retained (−) enantiomer may beracemized using any of the methods described in Example 4. Racemizationof the less retained enantiomer results in a more productive method toisolate the desired more retained enantiomer. Using racemization thereare two options to run the SMB separation process to enhanceproductivity, yield and optical purity. In the first option the moreretained enantiomer is mostly recovered in the extract and the solutionto be racemized contains almost exclusively the less retainedenantiomer. In the second option the more retained enantiomer is partlyrecovered in the extract and the solution to be racemized contains asignificant amount of both enantiomers.

[0055] When the first option is chosen the amount of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1 -ynyl)-phenyl]-1-methyl-1H-quinolin-2-one to be racemized is minimized, but when the secondoption is chosen it is possible to increase the SMB throughput andenhance the daily productivity of the process.

[0056] The two options were studied first by numerical simulations,which allow one to make a fast parametric study of the process. In thecase of the second option the recovery yield of the less retainedenantiomer in the raffinate was an additional parameter that could bevaried to achieve optimum performance. It was found that a recoveryyield of above 90% leads to a good compromise between the improvement ofthe SMB performance and the increase of the amount of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one to be racemized.

[0057] In the case of large-scale enantiomeric separations by SMB thecost of the purification is mainly linked to the productivity, theinfluence of the eluent consumption being secondary. Consequently, inthe present case where racemization is expected to be relativelyinexpensive, the second option has a clear advantage in increasing theSMB throughput and consequently an enhanced productivity.

[0058] A schematic depicting the SMB purification and racemization stepis shown below:

[0059] The more retained enantiomer (+) may be recovered at the requiredoptical purity (95-99.9%) in the extract stream whereas the lessretained enantiomer (+) may be collected in the raffinate stream. It maybe possible to recycle the stream enriched in the undesired enantiomerthrough a racemization unit, which would decrease the necessary amountof new racemic feed required.

[0060] Two examples of the SMB optimization follow which are optimizednear the 90-95% recovery of the (+) enantiomer considered to be optimumas described above.

[0061] Other enantiomeric separation techniques may also be employed toseparate the enantiomers of the racemate,6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one. One preferred method of separating the enantiomers ofthe racemate6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yi)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one is salt crystalization techniques.

[0062] The Dutch method of salt resolution screening (Broxterman et al.,Dutch Resolution, A New Technology in Classical Resolution, Chim. Oggi.16(9), 34-37, (1998)) may be used to determine the optimal chiral acidfor the resolution. In this method several chiral acids from a family(i.e., tartaric acid derivatives) were added to the free base6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yi)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one to be resolved. The organicsolvent screened in the process may be any such solvent in which thesalt formed from the6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one to be resolved and a chiralacid is soluble at elevated temperature but insoluble at ambienttemperatures. Exemplary of suitable solvents are methanol, ethanol,2-propanol, n- butanol, acetone, methyl ethyl ketone, ethyl acetate,t-butyl acetate, methylene chloride and mixtures thereof.

[0063] In a typical procedure a mixture of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1 -ynyl)-phenyl]-1 -methyl-1 H-quinol in-2-one and mixture of a familyof acids were dissolved in a solvent by the application of heat. Uponcooling to room temperature any crystals that formed were isolated.Analysis was performed using HPLC on the free base of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1 -ynyl)-phenyl]-l -methyl-1 H-quinolin-2-one which was obtained bytreatment of approximately 10 mg the salt of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-l -methyl-1 H-quinolin-2-one with 0.5M NaOH and EtOAc (1mL of both). The following are the conditions under which the HPLC wereperformed: CHIRALPAK® AD resin (manufactured by Daicel ChemicalIndustries, Ltd., Osaka, Japan); solvent system 30% isopropanol/70%heptane, UV 210 nm or 340 nm. The(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]- 1-methyl-1H-quinolin-2-one eluded after 5.6 minuteswhile the(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-oneeluded after 13.6 minutes. The HPLC method described above to determinethe presence of the desired enantiomer was also performed for Examplesof the present application. The e.r can be readily assertained bydividing the area of the enantiomer of interest by the total area of thetwo enantiomers.

[0064] The racemates, enantiomers, prodrugs, solvates and theirpharmaceutically acceptable salts (herein referred to as “the activecompounds”) exhibit activity as Ras farnesylation inhibitors and areuseful in the treatment of cancer and the inhibition of abnormal cellgrowth in mammals, including humans. The abnormal cell growth is cancer,including, but not limited to, lung cancer, bone cancer, pancreaticcancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, uterine cancer, ovarian cancer, rectal cancer,cancer, of the anal region, stomach cancer, colon cancer, breast cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, carcinoma of the cervix, carcinoma of the vagina, carcinomaof the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of thesmall intestine, cancer of the endocrine system, cancer of the thyroidgland, cancer of the parathyroid gland, cancer of the adrenal gland,sarcoma of soft tissue, cancer of the urethra, cancer of the penis,prostate cancer, chronic or acute leukemia, lymphocytic lymphomas,cancer of the bladder, cancer of the kidney or ureter, renal cellcarcinoma, carcinoma of the renal pelvis, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, spinal axis tumors, brainstem glioma, pituitary adenoma, or a combination of one or more of theforegoing cancers.

[0065] In another embodiment the abnormal cell growth is a benignproliferative disease, including, but not limited to, psoriasis, benignprostatic hypertrophy or restinosis. The racemates, enantiomers andtheir pharmaceutically acceptable salts are useful in inhibitingfarnesyl protein transferase.

[0066] The enantiomers of the present invention are basic in nature andare capable of forming a wide variety of different salts with variousinorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animals, it is oftendesirable in practice to initially isolate the active compound from thereaction mixture as a pharmaceutically unacceptable salt and then simplyconvert the latter back to the free base compound by treatment with analkaline reagent and subsequently convert the latter free base to apharmaceutically acceptable acid addition salt. The acid addition saltsof the base compounds of this invention are readily prepared by treatingthe base compound with a substantially equivalent amount of the chosenmineral or organic acid in an aqueous solvent medium or in a suitableorganic solvent, such as methanol or ethanol. Upon evaporation of thesolvent, the desired solid salt is readily obtained. The desired acidaddition salt can also be precipitated from a solution of the free basein an organic solvent by adding to the solution an appropriate mineralor organic acid. Cationic salts of the active compounds are similarlyprepared except through reaction of a carboxy group with an appropriatecationic salt reagent, such as sodium, potassium, calcium, magnesium,ammonium, N,N′-dibenzylethylenediamine, N-methylglucamine (meglumine),ethanolamine, tromethamine, or diethanolamine.

[0067] The active compounds of the present invention can be administeredorally, transdermally (e.g., through the use of a patch), parenterally,topically or rectally. Oral administration is preferred. In general,compounds are most desirably administered in dosages ranging from about1.0 mg up to about 500 mg per day, preferably from about 1 to about 100mg per day in single or divided (i.e., multiple) doses. The activecompounds will ordinarily be administered in daily dosages ranging fromabout 0.01 to about 10 mg per kg body weight per day, in single ordivided doses. Variations may occur depending on the weight andcondition of the person being treated and the particular route ofadministration chosen. In some instances, dosage levels below the lowerlimit of the aforesaid range may be more than adequate, while in othercases still larger doses may be employed without causing any harmfulside effect, provided that such larger doses are first divided intoseveral small doses for administration throughout the day.

[0068] The active compounds may be administered alone or in combinationwith pharmaceutically acceptable carriers or diluents by the routespreviously indicated, and such administration may be carried out insingle or multiple doses. More particularly, the active compounds can beadministered in a wide variety of different dosage forms, i.e., they maybe combined with various pharmaceutically acceptable inert carriers inthe form of tablets, capsules, lozenges, troches, hard candies, powders,sprays, creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, elixirs, syrups, and the like. Such carriers include soliddiluents or fillers, sterile aqueous media and various non-toxic organicsolvents, etc. Moreover, oral pharmaceutical compositions can besuitably sweetened and/or flavored.

[0069] For oral administration, tablets containing various excipientssuch as microcrystalline cellulose, sodium citrate, calcium carbonate,dicalcium phosphate and glycine may be employed along with variousdisintegrants such as starch (and preferably corn, potato or tapiocastarch), alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often very useful for tablettingpurposes. Solid compositions of a similar type may also be employed asfillers in gelatin capsules; preferred materials in this connection alsoinclude lactose or milk sugar as well as high molecular weightpolyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the active ingredient may be combinedwith various sweetening or flavoring agents, coloring matter or dyes,and, if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, ethanol, propylene glycol,glycerin and various like combinations thereof.

[0070] For parenteral administration, solutions of active compound ineither sesame or peanut oil or in aqueous propylene glycol may beemployed. The aqueous solutions should be suitably buffered if necessaryand the liquid diluent first rendered isotonic. These aqueous solutionsare suitable for intravenous injection purposes. The oily solutions aresuitable for intra-articular, intra-muscular and subcutaneous injectionpurposes. The preparation of all these solutions under sterileconditions is readily accomplished by standard pharmaceutical techniqueswell-known to those skilled in the art.

[0071] Additionally, it is also possible to administer the activecompounds topically and this may preferably be done by way of creams,jellies, gels, pastes, ointments and the like, in accordance withstandard pharmaceutical practice.

[0072] The active compounds may also be administered to a mammal otherthan a human. The dosage to be administered to a mammal will depend onthe animal species and the disease or disorder being treated. The activecompounds may be administered to animals in the form of a capsule,bolus, tablet or liquid drench. The active compounds may also beadministered to animals by injection or as an implant. Such formulationsare prepared in a conventional manner in accordance with standardveterinary practice. As an alternative the therapeutic compounds may beadministered with the animal feedstuff and for this purpose aconcentrated feed additive or premix may be prepared for mixing with thenormal animal feed.

[0073] The activity of the active compounds as Ras farnesylationinhibitors may be determined by their ability, relative to a control, toinhibit Ras farnesyl transferase in vitro. This procedure is describedbelow.

[0074] A crude preparation of human farnesyl transferase (FTase)comprising the cytosolic fraction of homogenized brain tissue is usedfor screening compounds in a 96-well assay format. The cytosolicfraction is prepared by homogenizing approximately 40 grams fresh tissuein 100 ml of sucrose/MgCI₂/EDTA buffer (using a Dounce homogenizer;10-15 strokes), centrifuging the homogenates at 1000×g for 10 minutes at4° C., re-centrifuging the supernatant at 17,000×g for 15 minutes at 4°C., and then collecting the resulting supernatant. This supernatant isdiluted to contain a final concentration of 50 mM Tris HCI (pH 7.5), 5mM DTT, 0.2 M KCI, 20 μM ZnCI₂, 1 mM PMSF and re-centrifuged at178,000×g for 90 minutes at 4° C. The supernatant, termed “crude FTase”was assayed for protein concentration, aliquoted, and stored at −70° C.

[0075] The assay used to measure in vitro inhibition of human FTase is amodification of the method described by Amersham LifeScience for usingtheir Farnesyl transferase (³H) Scintillation Proximity Assay (SPA) kit(TRKQ 7010). FTase enzyme activity is determined in a volume of 100 μLcontaining 50 mM N-(2-hydroxy ethyl) piperazine-N′-(2-ethane sulfonicacid) (HEPES), pH 7.5, 30 mM MgCI₂, 20 mM KCI, 25 mM Na₂HPO₄, 5 mMdithiothreitol (DTT), 0.01% Triton X-100, 5% dimethyl sulfoxide (DMSO),20 pg of crude FTase, 0.12 PM [3H]-farnesyl pyrophosphate ([³H]-FPP;36000 dpm/pmole, Amersham LifeScience), and 0.2 pM of biotinylated Raspeptide KTKCVIS (Bt-KTKCVIS) that is N-terminally biotinylated at itsalpha amino group and was synthesized and purified by HPLC in house. Thereaction is initiated by addition of the enzyme and terminated byaddition of EDTA (supplied as the STOP reagent in kit TRKQ 7010)following a 45 minute incubation at 37° C. Prenylated and unprenylatedBt-KTKCVIS is captured by adding 10 μL of steptavidin-coated SPA beads(RPNQ0007) per well and incubating the reaction mixture for 30 minutesat room temperature. The amount of radioactivity bound to the SPA beadsis determined using a MicroBeta 1450 plate counter. Under these assayconditions, the enzyme activity is linear with respect to theconcentrations of the prenyl group acceptor, Bt-KTKCVIS, and crudeFTase, and inhibition of Bt-KTKCVIS interaction with FTase can bedetected. The enzyme activity is saturating with respect to the prenyldonor, FPP. The assay reaction time is also in the linear range.

[0076] The test compounds are routinely dissolved in 100% DMSO.Inhibition of farnesyl transferase activity is determined by calculatingpercent incorporation of tritiated-farnesyl in the presence of the testcompound versus its incorporation in control wells (absence ofinhibitor). An IC₅₀ value, that is, the concentration required toproduce half maximal farnesylation of Bt-KTKCVIS, is determined for eachcompound from the dose-responses obtained.

[0077] The present invention is illustrated by the following Examples.It will be understood, however, that the invention is not limited by thespecific details of the following Examples.

EXAMPLE 1

[0078] Preparation of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one

[0079] A clean, dry, 500 gallon glass lined reactor was charged with 50Kg of (4-(3-Bromo-phenyl)-6-(4-chloro-benzoyl)-1-methyl-1H-quinolin-2-one) (110 moles, I eq) followed by 4.65 Kg ofBis(triphenylphosphine)palladium (II) chloride ( 6.63 moles, 0.06 eq)and 1.26 Kg Copper (I) Iodide ( 6.63 moles, 0.06 eq). Then charged 55gallons of TEA (1492 moles, 13.6 eq) and 110 gallons of THF (8.33V),this was followed by the addition of 13.9 Kg of 2-methyl -3-butyn-2-ol(165 moles, 1.5 eq). The stirred mixture was then heated to 60-65° C.for 18 hours, the reaction tank was attached to a scrubber tankcontaining aqueous sulfuric acid to reduce TEA odor, a slight positiveN2 stream is maintained to assure vapors migrate to the scrubber.

[0080] The reaction was cooled to 18-23° C. and sampled for HPLCanalysis and the reaction was deemed complete. Then charged to thereaction 16.5 Kg of Darco G-60 and 16.5 Kg of Filter aid (celite), theresulting mixture was stirred for 2 hours. The entire reaction mixturewas then filtered through a celite coated filter and the filter cakewashed with 55 gallons of THF (4.16V). The filtrate was charged to a 300gallon glass lined reactor and vacuum concentrated to a volume of˜130-135 gallons while maintaining a pot temperature of less than 65° C.The concentrate was then displaced with 330 gallons of1,2-Dichloroethane (25V) while still maintaining a pot temperature lessthan 65°C. At the end of the displacement a further 55 gallons of1,2-dichloroethane (4.2V) was added.

[0081] Then charged to the reactor an aqueous ammonium chloride solutionthat was pre-prepared by dissolving 50 Kg of ammonium chloride in 106gallons of water. The resulting mixture was stirred for 2 hours and thenthe layers were allowed to settle. The lower organic layer was removedand the upper ammonium chloride aqueous drummed up. The organic layerwas returned to the tank and charged an aqueous Sodium bicarbonate washthat was pre-prepared by dissolving 20 Kg of sodium bicarbonate in 106gallons of water. The resulting mixture was stirred for 2 hours and thenthe layers were allowed to settle. The lower organic layer was separatedand the aqueous layer drummed up. The organic layer was returned to thetank and the above aqueous sodium bicarbonate wash repeated.

[0082] After the layers are separated and the organic layer returned tothe tank, 106 gallons of fresh water was charged and the mixture stirredfor 2 hours. The layers were settled and separated and the organic layercharged back to the tank. The charged a pre-prepared solution of 50 KgSodium chloride dissolved in 106 gallons of water and stirred for 2hours. The layers were settled and separated and the organic layercharged to a clean, dry, 300 gallon glass lined reactor.

[0083] The DCE solution was then vacuum concentrated to 60-70 gallons,this concentrate was then vacuum displaced with 165 gallons of Toluenewhile maintaining a pot volume of 60- 70 gallons and a temperature lessthan 65° C. The resulting slurry was cooled to 18-23° C. and granulatedfor 6 hours.

[0084] The slurry was filtered and the solid filter cake washed with 15gallons of Toluene followed by 15 gallons of Hexane. The solids werevacuum dried at 40-45° C. for 15 hours, this resulted in 43.7 Kg of6-(4-Chloro-benzoyl)-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one) (86.7% yield).

[0085] To a clean, dry, glass lined reactor was charged 87 Kg of(5-bromo-1-methylimidazole mesylate salt, 338 moles, leq) and 86 gallonsof MTBE (methyl tert-butyl ether) (3.75V). Then charged 16 gallons ofwater (0.716V) and the stirred mixture was cooled to 10-15° C. Thenadded slowly to the cooled mixture 21 liters of 50% sodium hydroxide(1.2 eq) keeping the internal temperature below 24° C. When thisaddition was complete the mixture was stirred at ambient temperature for30-minutes. At this point the pH of the aqueous layer was seen to be13.0. The layers were allowed to settle and the lower aqueous layerseparated. The organic layer was drummed and the aqueous layer returnedto the tank along with 43 gallons of MTBE (1.87V) and the mixturestirred for 30 minutes. The layers were allowed to settle and the loweraqueous layer separated. The first drummed organic layer was returned tothe tank and combined with the MTBE backwash. To the organic layer wascharged 9 gallons of water and the mixture stirred for 30 minutes. Thelayers were allowed to settle and separated away the lower aqueouslayer. Then charged 8 gallons of saturated sodium chloride solution andstirred for 30 minutes. The layers were allowed to settle and the loweraqueous separated. The organic layer was charged to a clean, dry, 500gallon glass lined tank and added 27 Kg of anhydrous magnesium sulfateand stirred the resulting mixture for 3 hours. The spent drying agentwas filtered off and the filter cake washed with 10 gallons of MTBE. Theorganic filtrate was charged back to the tank and added 40 Kg of 4Amolecular sieves and the mixture slowly stirred for 20 hours. Themixture was filtered and the filtrate sent to a clean, dry, and nitrogenpurged 500 gallon glass lined tank, the filter cake was washed with 10gallons of MTBE.

[0086] To a clean, dry, and nitrogen purged 500 gallon glass linedreactor charged 200.4 Kg of the 5-bromo-2-methylimidazole free basesolution in MTBE (as described above). This contained 22.3 Kg (138moles, 4 eq) of the imidazole free base. This solution was vacuumstripped to an oil maintaining an internal temperature of 20-250C. Thecharge to the concentrated oil, 6 gallons of THF (1.42 V) and 165gallons of methylene chloride (40 V) and the resulting mixture stirredto obtain a solution.

[0087] Then slowly charged to the reaction mixture over 55 minutes, 116Kg (37 gallons) of 1.0 Molar ethyl magnesium bromide in MTBE (138 moles,4 eq), while keeping the internal temp below 24° C. The reaction wasthen stirred at 15-24° C. for 8 hours. The reaction was sampled for HPLCanalysis and the grignard formation was deemed complete.

[0088] Then charged slowly to the grignard reaction mixture, 15.8 Kg ofCP-729,134 ( 34.6 moles, 1 eq) dissolved in 59 gallons of methylenechloride (14 V) keeping the internal temperature below 250C. Theaddition of this solution took 30 minutes. The charge tank was rinsedwith 21 gallons of methylene chloride (5 V) and this rinse charged tothe reaction mixture. The entire reaction mixture was then heated to40-45° C. for 8 hours. After cooling to 20-25° C. the reaction wassampled for HPLC analysis and the reaction deemed complete.

[0089] Then charged to the reaction mixture over 30 minutes a solutionof 80.2 Kg of ammonium chloride dissolved in 156 gallons of water. Thebiphasic mixture was stirred for 30 minutes, the layers allowed tosettle and separated. The organic layer was returned to the tank and 156gallons of fresh water charged. The layers were stirred for 30 minutes,allowed to settle, and the layers separated. The organic layer wascharged to a clean, dry, 500 gallon glass lined reactor and then heatedto atmospherically distilled of methylene chloride until a volume of18-20 gallons was reached.

[0090] This resulted in a slurry, the temperature was allowed to cool to15-20° C. and the slurry granulated for 2 hours. The solids werefiltered off and the filter cake washed with 10 gallons of methylenechloride.

[0091] The isolated solids were vacuum dried at 40-45° C. for 16 hours,this gave 16.4 Kg of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one (88% yield). This material was 99.7% pure byHPLC area percent.

EXAMPLE 2

[0092] HPLC Batch Chromatography

[0093] 240 grams of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-onewas dissolved in 9.45 liters of a 70/30/0.1 mix ofheptane/isopropanol/diethylamine. Approximately 1.3 liters of thissolution was then loaded onto a 15 cm x 25 cm column packed withCHIRALPAK® AD resin (manufactured by Daicel Chemical Industries, Ltd.,Osaka, Japan). The column was eluted with the same solvent mix as thefeed was dissolved in at a flow rate of 1000 ml/min. The effluent wasmonitored at 310 nm. Two distinct peaks were collected. The cycle ofloading and eluting was repeated until all 9.45 liters were separated. Acomposite containing the cuts of the early eluting enantiomer(−)-6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1H-quinolin-2-one was made and concentrated todryness to give 115 grams of solids which had and enantiomeric excess of98%. A composite of the cuts from the second eluting enantiomer(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1H-quinolin-2-one was made and alsoconcentrated to dryness to give 115 grams of solids which had anenantiomeric excess of 97%. The yield to both enantiomers was about 96%of theory. The productive yield of the process described above was about0.5 kg of enantiomer produced per kg of chiral stationary phase per day.

[0094] In contrast using batch HPLC separation of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1 H-quinolin-2-one as described in the '377 patent gives aproductivity of only 0.0093 kg of enantiomer per kg of chiral stationaryphase per day. The process for separation of enantiomers of6-[(4-Chloro-phenyl)-hydroxy-5(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one is over 500 times moreproductive than the process employed to separate racemic6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one. Use of the present process provides significantcommercially advantages including lower cost, smaller columns, andemployment of less 10 resin for separation, which results in largesavings in production costs.

EXAMPLE 3

[0095] Separation of enantiomers of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one Using SMB withHeptane/Ethanol Mobile Phase

[0096] The racemate,6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one was separated using the SMBprocess described in the specification. The eluent employed was a 50:50mixture of ethanol and heptane. The SMB operating parameters employedare shown in the following TABLE 2 Column: (CSP) CHIRALPAK ™ AD MobilePhase: 50% ethanol/ 50% heptane Column Length: 10.7 cm Column I.D.: 5.0cm Number of Columns: 6 columns Feed Concentration 12 gms/liter EluentFlow-rate 200 ml/min Feed Flow Rate: 81 ml/min Flow Rate in Zone I: 347ml/min Extract Flow Rate: 179 ml/min. Raffinate Flow Rate 102 ml/min.Period 1.37 min Temperature 25° C. Operating pressure 55 bars

[0097] The performance characteristics using SMB are shown in Table 3below. The SMB process provides a productivity of 0.76 kg of enantiomerper day per kilogram of the chiral stationary phase employed. TABLE 3SMB PERFORMANCE CHARACTERISTICS More retained enantiomer purity (%) 99.5More retained enantiomer recovery yield (%) 92.5 Calculated volume ofeluent necessary 0.62 (l/g enantiomer) Productivity 0.76 (kgenantiomer/day/kg Chiral Stationary Phase) Amount of feed to beprocessed 2.16 (g/g enantiomer recovered) Amount of product to beracemized 1.16 (g/g enantiomer recovered)

EXAMPLE 4

[0098] Separation of enantiomers of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1 -ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one Using SMB withEthanol/Methanol Mobile Phase

[0099] The racemate, 6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one,was separated using the SMB process as described in the specificationusing a 50:50 mixture of heptane and ethanol as the eluent. The SMBoperating parameters employed are shown in the following TABLE 4 SMBOPERATING PARAMETERS Type of Chiral Column: CHIRALPAK ™ AD Mobile Phase:50/50 v/v ethanol/methanol # Columns 6 Column Length: 10.7 cm ColumnI.D.: 5.0 cm Feed Concentration (g/liter) 20 Feed Flow Rate: (ml/min) 26Eluent Flow-rate (ml/min) 197 Flow Rate in Zone I 415.3 ml/min ExtractFlow Rate: (ml/min) 168.4 Raffinate flow rate (ml/min) 54.6 Period 0.79Temperature 25° C. Pressure (bar) 40

[0100] The performance characteristics using SMB with theheptane/ethanol mixture are shown in Table 5 below. Compared to Example3 this SMB process is not as productive, however, there is a decrease inthe amount of eluent required per gram of the enantiomer. Accordingly,this process requires less solvent while still being a very productiveway of preparing6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1 -methyl-1 H-quinolin-2-one. TABLE 5 SMB PERFORMANCECHARACTERISTICS More retained enantiomer purity (%) 99.4 More retainedenantiomer recovery yield (%) 95 Calculated volume of eluent necessary(liter/gm 0.60 enantiomer) Productivity (kg enantiomer per day per KgCSP) 0.63 Amount of feed to be processed (Kg per Kg 2.10 enantiomerrecovered) Amount of product to be racemized (Kg per Kg 1.10 enantiomerrecovered)

EXAMPLE 5

[0101] Racemization Processes For(−)-6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one

[0102](−)-6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-onemay be racemized using any of the following methods (A)-(C). However,Method A is preferred over Methods B or C, since it results in completeracemization.

[0103] Method A

[0104] The less retained enantiomer[(−)-6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl )-phenyl]-1 -methyl-1H-quinolin-2-one] was dissolved in 3 volumesof dimethyl formamide/water (5/1 mix). One volume of p-toluenesulfonicacid was added and complete racemization was seen after 4 hours.

[0105] Method B

[0106] The (−) enantiomer was dissolved in 10 volumes of a 5/1 mix oftoluene and water. One volume of formic acid was added and the solutionwas refluxed for 14 hours. The analysis showed 40% of the (+)enantiomer.

[0107] Method C

[0108] 10 volumes of a 10/1 mix of tetrahydrofuran and water were addedto the (−) enantiomer and 1 volume of trifluoroacetic acid was added andthe mixture was refluxed for 3 days. The solution was then analyzed andfound to have 14% of the (+) enantiomer.

EXAMPLE 6

[0109] Salt Resolution of6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinol in-2-one Using L-(+)-Tartaric Acid

[0110] 100 gms of racemic,6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1 -ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one (0.186 moles) and 27.9 gmsof (+)-2,3-dihydroxy butanedioate (0.186 moles, 1 eq ) was added to a3-neck round bottom flask fitted with mechanical stirring, refluxcondenser, thermocouple probe and a heating mantel. To the abovereactants was added 2,300 mis of 2-propanol and 23 mis of water and theresulting white slurry heated. As the mixture was heated, solids wereseen to dissolve, at reflux the solution was a slight haze. Heating wasstopped and the mixture allowed to slowly cool. At 65° C. 20 mg of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one, (+)-2,3-dihydroxybutanedioate (e.r. 99:1) seed was added and cooling/crystallizationcontinued. When the reaction mixture reached ambient temperature theresulting white slurry was granulated for 5 hours. The solids wereisolated by vacuum filtration and the filter cake washed with 50 mis ofdry 2-propanol, the solids were vacuum dried at 40-45° C to give 53.1gms (41.5% overall yield) of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one,(+)-2,3-dihydroxybutanedioate. Using chiral HPLC as described in the specification showedan e.r. of 96.3 : 3.6. NMR indicates ˜3% 2-propanol present. Opticalrotation of +32.9°in methanol using Na light source with a 1 decimetercell (c=1 .1013 gm/100 mis).

EXAMPLE 7

[0111] Repulp of (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1 -ynyl)-phenyl]-1 -methyl-1 H-quinol in-2-one, (+)-2,3-dihydroxybutanedioate to improve e.r.

[0112] 2 gms of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one, (+)-2,3-dihydroxybutanedioate with a e.r. of 97.2 : 2.8 was slurried in 30 mIs (15V) ofdry 2-propanol for 4-5 hours. The solids are isolated by vacuumfiltration and washed with a small amount of dry 2- propanol. Aftervacuum drying the solids overnight at 40-45° C. 1.8 gms of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yL)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one, (+)-2,3-dihydroxybutanedioate was recovered (90% mass recovery). Using chiral HPLC asdescribed in the specification showed an e.r. of 99.2:0.8.Photomicrograph analysis of salts showed both isomers to be crystalline.NMR analysis of the salts confirms a 1:1 adduct of substrate toresolving agent.

EXAMPLE 8

[0113] Salt Resolution of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one Using(S)-(-)-1,1′-binapthyl-2,2′-diyl hydrogenphosphate 200 mg of racemic6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-onewas combined with 80-140 mg of (S)-(−)-1,1′-binapthyl-2,2′-diylhydrogenphosphate (S-BINAP). The solids were diluted with 3-5 ml ofeither 10% acetone: 90% ethyl acetate or 20% acetone: 80% ethyl acetate.The mixture was stirred at 60° C for 16 hours. The solids were filteredand dried in vacuo for 16 hours at 40° C to recover(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2- one,(−)-1,1′-binapthyl-2,2′-diyl hydrogenphosphate. The solids were thenrecombined of either 10% acetone: 90% ethyl acetate or 20% acetone: 80%ethyl acetate and stirred at 60° C. for 16 hours. The solids werefiltered and dried as before. The repulps were continued until thedesired chiral purity was achieved.

[0114] The following table shows the weight recoveries and chiralpurities for(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one, (−)-1,′-binapthyl-2,2′-diyl hydrogenphosphate following repeated repulpingusing the process described above. Salt Repulp Repulp Repulp RepulpSolvent Overall Formation 1 2 3 4 Yield Yield 115.60% 81.40% 86.50%  90% 82.30% 10%:90% 60.30% Chiral 68.50% 83.00% 89.60% 92.20% 94.00%Acetone:EtOAc Purity Yield 95.60% 77.40% 57.20%   88% 89.60% 20%:80%33.70% Chiral 73.90% 89.10% 94.60% 95.90% 96.60% Acetone:EtOAc Purity

[0115] It should be understood that the invention is not limited to theparticular embodiments described herein, but that various changes andmodification may be made without departing from the spirit and scope ofthis novel concept as defined by the following claims.

What is claimed is:
 1. A compound selected from the group consisting of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one and(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one, prodrugs thereof andpharmaceutically acceptable salts and solvates of said compounds andprodrugs.
 2. The compound of claim 1, wherein said compound is(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one.
 3. The compound of claim 1,wherein said compound is(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one.
 4. The compound of claim 1,wherein said pharmaceutically acceptable salts are selected from thegroup consisting of L-(+)-tartaric acid and(S)-(−)-1,1′-binapthyl-2,2′-diyl hydrogenphosphate.
 5. The compound ofclaim 1, wherein said compound is(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one, L-(+)-tartaric acid.
 6. Thecompound of claim 1, wherein said compound is(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one,(S)-(−)-1,1′-binapthyl-2,2′-diyl hydrogenphosphate.
 7. A method for thetreatment of abnormal cell growth in a mammal comprising administeringto said mammal an amount of a compound according to claim 1 that iseffective in inhibiting farnesyl protein transferase.
 8. A methodaccording to claim 7, wherein said abnormal cell growth is cancer.
 9. Amethod according to claim 8, wherein said cancer comprises lung cancer,bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck,cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,rectal cancer, cancer of the anal region, stomach cancer, colon cancer,breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocyiic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of two or more of the foregoing cancers.
 10. A methodaccording to claim 8, wherein said abnormal cell growth is a benignproliferative disease.
 11. A method according to claim 10, wherein saidbenign proliferative disease comprises psoriasis, benign prostatichypertrophy, or restinosis.
 12. A method for the treatment of abnormalcell growth in a mammal which comprises administering to said mammal atherapeutically effective amount of a compound according to claim 1 incombination with an anti-tumor agent selected from the group consistingof mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, and anti-androgens.
 13. A method for thetreatment of abnormal cell growth in a mammal comprising administeringto said mammal an amount of a compound according to claim 1 that iseffective in treating abnormal cell growth.
 14. A pharmaceuticalcomposition for the treatment of abnormal cell growth in a mammal whichcomprises an amount of a compound according to claim 1 that is effectivein inhibiting farnesyl protein transferase and a pharmaceuticallyacceptable carrier.
 15. A pharmaceutical composition according to claim1, wherein said abnormal cell growth is cancer.
 16. A pharmaceuticalcomposition according to claim 15, wherein said cancer comprises lungcancer, bone cancer, pancreatic cancer, skin cancer, cancer of the heador neck, cutaneous or intraocular melanoma, uterine cancer, ovariancancer, rectal cancer, cancer of the anal region, stomach cancer, coloncancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers.
 17. Apharmaceutical composition according to claim 16, wherein said abnormalcell growth is a benign proliferative disease.
 18. A pharmaceuticalcomposition according to claim 17, wherein said benign proliferativedisease comprises psoriasis, benign prostatic hypertrophy, orrestinosis.
 19. A pharmaceutical composition for the treatment ofabnormal cell growth in a mammal which comprises an amount of a compoundaccording to claim 1 that is effective in treating abnormal cell growthand a pharmaceutically acceptable carrier.
 20. A pharmaceuticalcomposition for the treatment of abnormal cell growth in a mammal whichcomprises a therapeutically effective amount of a compound of claim 1 incombination with a pharmaceutically acceptable carrier and an anti-tumoragent selected from the group consisting of mitotic inhibitors,alkylating agents, anti-metabolites, intercalating antibiotics, growthfactor inhibitors, cell cycle inhibitors, enzymes, topoisomeraseinhibitors, biological response modifiers, anti-hormones, andanti-androgens.
 21. A method for the treatment of an infection in amammal, wherein said infection is facilitated by farnesyl proteintransferase, which comprises administering to said mammal atherapeutically effective amount of a compound of claim
 1. 22. Themethod of claim 21, wherein said infection is hepatitis delta virus ormalaria.
 23. A pharmaceutical composition for the treatment of aninfection in a mammal, wherein said infection is facilitated by farnesylprotein transferase, which comprises a therapeutically effective amountof a compound of claim 1 and a pharmaceutically acceptable carrier. 24.The pharmaceutical composition of claim 23, wherein said infection ishepatitis delta virus or malaria.
 25. A process for chromatographicallyresolving6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-i-ynyl )-phenyl]-1-methyl-1H-quinolin-2-one using continuouschromatography, the continuous chromatography comprising a liquid mobilephase comprising a least one polar solvent and a solid chiral stationaryphase comprising a derivatized polysaccharide that is selected from theamylosic and cellulosic class of polysaccharides.
 26. The processaccording to claim 25, wherein the chromatographic method employed is aselected from the group consisting of simulated moving bedchromatography, high performance liquid chromatograph and cyclojetprocess.
 27. The process according to claim 26, wherein thechromatographic method is simulated moving bed chromatography.
 28. Theprocess according to claim 26, wherein the chromatographic method ishigh performance liquid chromatograph.
 29. The process according toclaim 28, wherein the solid chiral stationary phase is an amylosicpolysaccharide.
 30. The process according to claim 29, wherein the solidchiral stationary phase is selected from amylose 3, 4-substituted phenylcarbamate, cellulose 3, 5-substituted phenyl carbamate or cellulose4-substituted benzoate.
 31. The process according to claim 30, whereinthe chiral stationary phase is an analog of amylose tris(3,5-substituted phenyl carbamate) wherein the substituent is 3,5-dimethyl.
 32. A process for the production of enantiomerically pure oroptically enriched6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one using simulated moving bedchromatography, the moving bed chromatography comprising a liquid mobilephase comprising a least one polar solvent and a solid chiral stationaryphase comprising a derivatized polysaccharide that is selected from theamylosic and cellulosic class of polysaccharides.
 33. The process ofclaim 32, wherein the chiral stationary phase is selected from amylose3, 4-substituted phenyl carbamate, cellulose 3, 5-substituted phenylcarbamate or cellulose 4-substituted benzoate.
 34. The process of claim33, wherein the chiral stationary phase is an analog of amylose tris(3,5-substituted phenyl carbamate) wherein the substituent is 3,5-dimethyl.
 35. The process of claim 33, wherein the chiral stationaryphase is a cellulose 3, 5-substituted phenyl carbamate or cellulose4-substituted benzoate polysaccharide analog.
 36. The process of claim33, wherein the mobile phase comprises a solvent that is selected fromheptane, hexane, isopropanol, ethanol, methanol, methyl acetate,acetonitrile, methylene chloride, ethyl acetate and/or mixtures thereof.37. The process of claim 36, wherein the mobile phase is selected fromheptane and ethanol or isopropanol and/or a mixture of methanol andethanol with or without heptane.
 38. The process of claim 25, whereinthe polysaccharide derivative is immobilized on silica gel, zirconium,alumina, ceramics and other silicas.
 39. The process of claim 25, usingan amylose 3,4-substituted phenyl carbamate derivative polysaccharideanalog with a mobile phase of a mixture of heptane and ethanol ormethanol and ethanol.
 40. The process of claim 35, using an amylose tris(3,5-substituted phenyl carbamate) with a mobile phase of a mixture ofheptane and ethanol.
 41. The process of claim 36, using an amylose tris(3,5-substituted phenyl carbamate) with a mobile phase of mixture ofethanol and methanol wherein the percentage of ethanol and methanol are1:1 (v/v).
 42. The process of claim 25, wherein retention times areincreased or decreased by varying the mobile phase components.
 43. Theprocess of claim 25, wherein said separation affords at least one of theenantiomers a recovery of greater than or equal to 90%.
 44. The processof claim 25, using a tem perature range of about 5 to 45° C.
 45. Theprocess of claim 44, using a temperature range of about 20 to 40° C. 46.The process of claim 25, wherein the separation factor a is about 1.2 to5.0
 47. The process of claim 46, wherein using a temperature of about25° C. takes
 47. The process of claim 46, wherein using a temperature ofabout 25°C. takes advantage of increased solubility of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1H-quinolin-2-one in the mobile phase.
 48. Aprocess for preparing(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1H-quinolin-2-one, L-(+)-tartaric acidcomprising treating6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one with L-(+)-tartaric acid.49. The process of claim 48, wherein said process is carried out in amixture of propanol and water.
 50. The process of claim 49, whereinoptically enriched(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one, L-(+)-tartrate seed is added to the mixture.
 51. Theprocess of claim 50, wherein said mixture is cooled and crystallized.52. The process of claim 49, wherein said propanol is 2-propanol.
 53. Aprocess for preparing(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1 -methyl-1 H-quinolin-2-one,(S)-(−)-1,1′-binapthyl-2,2′-diyl hydrogenphosphate comprising treating6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one with (S)-(−)-1,1′-binapthyl-2,2′-diyl hydrogenphosphate.
 54. The process of claim 53,wherein said process is carried out in a mixture of acetone and ethylacetate.
 55. The process of claim 54, wherein solids were filtered anddried in vacuo.
 56. The process of claim 55, wherein said dried solidsare recombined with acetone and ethyl acetate.
 57. The process of claim56, wherein said mixture is stirred for 1 to 24 hours.
 58. The processof claim 57, wherein said mixture is filtered to isolate solids.
 59. Theprocess of claim 58, wherein said solids are dried in vacuo.